It is currently believed that proteolysis of the lung by proteases released by human leukocytes marks the onset of pulmonary emphysema. Human leukocyte elastase and cathepsin G are the serine proteases that have been implicated in the etiology of emphysema. The primary objectives of the proposed research project are: a) the design and synthesis of several new mechanism-based inhibitors of human leukocyte elastase and cathepsin G; b) the utilization of the synthesized compounds for in vitro enzyme inhibition studies in order to ascertain the efficacy and biospecificity of the synthesized compounds; c) the utilization of the synthesized compounds in gaining a better understanding of the make up of the active site of human leukocyte elastase and cathepsin G; and d) in vivo pharmacologic studies related to the ability of the synthesized compounds in alleviating elastase-induced emphysema in hampsters. The rationale behind the design of each class of inhibitor is explained and preliminary experimental evidence is adduced to support the ideas expounded in this proposal. Our primary long-term objective is the development of compounds that can be used as drugs for the treatment of emphysema and related ailments.